Method of treating metabolic disorders and depression with dopamine receptor agonists

ABSTRACT

This invention relates to methods and formulations for treating metabolic disorders and depression. In some embodiments, the methods comprise administering a dopamine receptor agonist and an anti-depressant.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/945,555, filed Jun. 21, 2007, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to methods for simultaneously treating metabolicdisorders and depression with dopamine receptor agonists.

BACKGROUND OF THE INVENTION

Dopamine agonists have been useful in the treatment of various diseasessuch as migraine headache, Parkinson's disease, acromegaly,hyperprolactinemia, prolactinoma, galactorrhea, amenorrhea, andmetabolic disorders, including diabetes.

Diabetes, one of the most insidious of the major diseases, can strikesuddenly or lie undiagnosed for years while attacking the blood vesselsand nerves. Diabetics, as a group, are far more often afflicted withblindness, heart disease, stroke, kidney disease, hearing loss, gangreneand impotence. One third of all visits to physicians in the U.S. areoccasioned by this disease and its complications, and diabetes and itscomplications are a leading cause of death in the U.S. and othercountries.

Diabetes adversely affects the way the body uses sugars and starcheswhich, during digestion, are converted into glucose. Insulin, a hormoneproduced by the pancreas, makes the glucose available to the body'scells for energy. In muscle, adipose (fat) and connective tissues,insulin facilitates the entry of glucose into the cells by an action onthe cell membranes. The ingested glucose is normally metabolized in theliver to CO₂ and H₂O (50%); to glycogen (5%), and to fat (30-40%), whichis stored in fat depots. Fatty acids are circulated, returned to theliver and metabolized to ketone bodies for utilization by the tissues.The fatty acids are also metabolized by other organs, fat formationbeing a major pathway for carbohydrate utilization. The net effect ofinsulin is to promote the storage and use of carbohydrates, protein andfat. Insulin deficiency is a common and serious pathologic condition inhumans. In Type 1 diabetes the pancreas produces little or no insulin,and insulin must be injected daily for the survival of the diabetic. InType 2 diabetes the pancreas produces insulin, but the amount of insulinis insufficient, or less than fully effective due to cellularresistance, or both. In either form there are widespread abnormalities,but the fundamental defects to which the abnormalities can be traced are(1) a reduced entry of glucose into various “peripheral” tissues and (2)an increased liberation of glucose into the circulation from the liver(increased hepatic glucogenesis). There is therefore an extracellularglucose excess and an intracellular glucose deficiency which has beencalled “starvation in the midst of plenty.” There is also a decrease inthe entry of amino acids into muscle and an increase in lipolysis. Thus,these result, as a consequence of the diabetic condition, in elevatedlevels of glucose in the blood, and prolonged high blood sugar, which isindicative of a condition which will cause blood vessel and nervedamage. Obesity, or excess fat deposits, is often associated withincreasing cellular resistance to insulin, which precedes the onset offrank diabetes. Prior to the onset of diabetes, the pancreas of theobese are taxed to produce additional insulin; but eventually, perhapsover several years prior to the onset of frank type 2 diabetes, insulinproductivity falls and diabetes results.

Obesity and insulin resistance, the latter of which is generallyaccompanied by hyperinsulinemia or hyperglycemia, or both, are hallmarksof Type 2 diabetes. Controlled diet and exercise can produce modestresults in the reduction of body fat deposits. Hyperinsulinemia is ahigher-than-normal level of insulin in the blood. Insulin resistance canbe defined as a state in which a normal amount of insulin produces asubnormal biologic response. In insulin-treated patients with diabetes,insulin resistance is considered to be present whenever the therapeuticdose of insulin exceeds the secretory rate of insulin in normal persons.Insulin resistance is also found in the setting defined byhigher-than-normal levels of insulin—i.e., hyperinsulinemia—when thereare present normal or elevated levels of blood glucose.

Insulin is a hormone with a multitude of biological activities, many ofwhich are tissue-specific. For example, insulin can augment milkproduction in the mammary gland, stimulate fat synthesis in the liver,promote the transport of glucose into muscle tissue, stimulate growth ofconnective tissues, and the like. The effects of the insulin molecule inone tissue are not necessarily dependent upon its effect in othertissues. That is, these insulin activities can be and are molecularlyseparate from each other. Dopamine receptor agonists (e.g.,bromocriptine) are known to inhibit liver cell lipogenic (or fatsynthesizing) responsiveness to insulin. But, appropriately timed dailyadministration of a dopamine agonist (e.g., bromocriptine) can be usedto stimulate whole body (primarily muscle) tissue hypoglycemic (orglucose disposal) responsiveness to insulin, as described in U.S. Pat.No. 5,468,755, incorporated herein by reference in its entirety.

Many of the hormones involved in metabolic disorders, includingdiabetes, exhibit a daily rhythm of fluctuating serum levels. Suchhormones include adrenal steroids, e.g., the glucocorticosteroids,notably cortisol, and prolactin, a hormone secreted by the pituitarygland. These daily rhythms provide useful indices for understanding andtreating metabolic diseases. For example, peak concentration ofprolactin occurs at different times of day in lean and fat animals.

The normal daily prolactin level profile of a healthy human is highlyregular and reproducible, characterized by a low and relatively constantday level followed by a sharp night-time peak, returning to a low levelby daytime. See U.S. Pat. No. 5,679,685, the contents of which areincorporated herein by reference. Altering the prolactin profile of asubject having a metabolic disorder or key element thereof to resemblethat of a healthy subject of the same species and sex can providetherapeutic benefit to the subject. The circadian rhythm of plasmaprolactin level “feedsback” centrally to reset circadian dopaminergicactivities that are critical in regulating peripheral glucose, lipid,and protein metabolism. Phase shifts in the circadian rhythm of dopaminerelease at the biological clock (the suprachiasmatic nuclei), from thatobserved in obese, insulin resistant animals to that observed in lean,insulin sensitive animals produces the lean insulin sensitive state.Dopamine agonists are useful agents for treatment of metabolic diseaseand/or key elements of metabolic disease and can be used to reset dailyprolactin profiles in subjects with metabolic disease and/or exhibitingkey elements thereof to that of healthy humans.

Previous studies have demonstrated that dopamine receptor agonists whenadministered at a predetermined time of day, generally in the morning inhumans, can improve metabolic disorders including obesity, insulinresistance, glucose intolerance, impaired fasting glucose, metabolicsyndrome, and Type 2 diabetes. It is also generally well-accepted thatdopamine is a mood enhancer. It is well-established that approximately30% of Type 2 diabetics have some form of clinical depression. Also,depression can be very common among obese patients and post-myocardialinfarction patients. Moreover, anti-depressant medication use appears tobe associated with diabetes risk (Diabetes Care, 31:420, 2008). Therelationship between metabolic disorders such as Type 2 diabetes anddepression, whether cause-effect or associational, has been the focus ofmuch research and debate. It is clear that the coexistence of thesedisorders hampers the effective treatment of either disorder andtherefore adversely influences the quality of life of these typepatients. But, co-treatment of metabolic disorders and depression can bedifficult insofar as most serotonin-enhancing anti-depressants andtricyclic anti-depressants that increase prolactin release potentiate orexacerbate metabolic disorders such as obesity, insulin resistance, andType 2 diabetes.

There is a need in the art for methods of treating both metabolicdisorders (including Type 2 diabetes) and depression. Accordingly, themethods of disclosed herein avoid problems associated with prior artapproaches and improve the treatment of metabolic disorders anddepression in patients suffering from both types of conditions. Themethods disclosed herein avoid or reduce problems such as, e.g., theadverse effects of serotonin-enhancing anti-depressants on metabolicdisorders, by treatment or co-treatment with one or more dopamineagonists. This co-treatment with one or more dopamine receptor agonistsfurther allow for the reduction in dose of serotonin-enhancinganti-depressants and thereby reduce their negative impact on metabolismand metabolic disorders.

SUMMARY OF THE INVENTION

In certain embodiments, the invention provides a method for treating ametabolic disorder and depression comprising administering to a patientin need thereof a therapeutically effective amount of one or moredopamine receptor agonists.

In certain embodiments, the invention provides a method of treating ametabolic disorder and depression comprising administering to a patientin need thereof a therapeutically effective combination of a dopaminereceptor agonist and an anti-depressant. Preferably, the dopaminereceptor agonist is administered at a first predetermined time of day,e.g., in the morning, and the anti-depressant is administered at asecond predetermined time of day, e.g., in the evening.

In certain embodiments, the metabolic disorder to be treated is Type 2diabetes, obesity or cardiovascular disease.

In another embodiment, the dopamine receptor agonist is bromocriptine.

In another embodiment, the invention provides a dosage form comprising afirst active agent and a second active agent, wherein said first activeagent is an anti-depressant, said second active agent is a dopamineagonist, said first active agent is substantially released within 2hours following administration of said dosage form and said secondactive agent is released substantially within the period within 2 hoursof waking when said dosage is administered at bedtime.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are methods for treating one or more metabolicdisorders (such as Type 2 diabetes) and depression, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a dopamine agonist and an anti-depressant.

Dopamine receptor agonists, when administered at the appropriate time ofday, have the ability to improve both metabolic disorders, such as Type2 diabetes, and depression. Moreover, in some cases, antidepressantmedications may be reduced when used at the appropriate time of day inconjunction with dopamine receptor agonists and resultantly improvemetabolic status, inasmuch as most serotonin-enhancing anti-depressantsand prolactin-enhancing anti-depressants such as the tricyclicspotentiate or exacerbate metabolic disorders such as obesity, insulinresistance, and Type 2 diabetes. That is, abnormal elevations in daytime(diurnal: 0500-2200) levels (versus nighttime levels) of centralneuronal synaptic serotonin (e.g., SSRIs) or postsynaptic serotonergicactivity or of plasma prolactin via pharmaceutical therapy maypotentiate both the depressed state and metabolic disease, in fact thedisorders such current standard treatment is aimed at ameliorating. Theapproach of the present invention is contrary to this approach and itsresults are contrary to the results of this approach.Serotonin-enhancing antidepressant agonists include agents that increasesynaptic levels of serotonin (e.g., serotonin itself, serotoninprecursors such as 5-hydroxy tryptophan or tryptophan, and selectiveserotonin reuptake inhibitors [SSRIs] and/or agents that increasepost-synaptic serotonin function (e.g., post-synaptic serotonin receptoragonists). Furthermore, appropriately timed daily administration ofdopamine receptor agonists and serotonin-enhancing anti-depressants mayfurther improve (i.e., maximize) the interactive effectiveness of bothto improve metabolic disease, such as Type 2 diabetes and depression.Generally, to achieve such a result, the dopamine receptor agonist wouldbe given in the morning upon waking and the serotonin-enhancinganti-depressant would be given later in the day, possibly preferably inthe evening before bedtime. In addition, administration of dopaminereceptor agonists to treat depression in individuals with Type 2Diabetes avoids side effects associated with the administration ofanti-depressant dopamine/norepinephrine re-uptake inhibitors (dopaminere-uptake inhibitors that also inhibit re-uptake of norepinephrine frompresynaptic neurons), via their influence to raise levels of synapticnorepinephrine, which could have negative metabolic health consequencesin individuals with metabolic disorders such as obesity, cardiovasculardisease and type 2 diabetes. The present invention avoids thecomplication and metabolic damage of increasing neuronal synapticnorepinephrine level while effectively treating metabolic disorders anddepression and in many cases the present invention may reduce abnormallyelevated neuronal synaptic norepinephrine level towards normal levelsobserved in healthy subjects. Elevated hypothalamic neuronal synapticnorepinephrine levels are believed to contribute to metabolic diseaseand therefore avoiding such an increase, as with dopamine receptoragonist therapy, is a benefit over those therapies that do increasesynaptic norepinephrine levels.

The present invention provides methods of improving metabolic disordersand depression in subjects in need of such treatment by increasingabnormally low daytime dopaminergic neuronal activity (e.g., withdopamine receptor agonist therapy) and inhibiting or avoiding increasesin daytime plasma prolactin and central synaptic serotonin levels andincreasing nighttime central serotonin levels or neuronal activityand/or plasma prolactin levels. This method is not employed by anyexisting standard therapies for the treatment of metabolic disorders anddepression.

Examples of dopamine receptor agonists may be non-ergot or ergot-relatedderivatives. These include D₁ dopamine receptor agonists and/or D₂dopamine receptor agonists.

The methods disclosed herein may comprise administration of one or moreD₁ dopamine receptor agonists and/or D₂ dopamine receptor agonists.

Therapeutically effective amounts of dopamine receptor agonist forhumans and other vertebrates vary according to several factors,including patient characteristics and route of administration. Forexample, therapeutically effective amounts of D₂ agonist for humans andvertebrates when administered parenterally alone (not conjoined to a D₁agonist) are typically within the range of about 0.5 μg/kg/day to about300 μg/kg/day. Preferably, the therapeutically effective amounts of D₂agonist for humans and vertebrates when administered alone are typicallywithin the range of about 0.5 μg/kg/day to about 250 μg/kg/day. Morepreferably, the therapeutically effective amounts of D₂ agonist forhumans and vertebrates when administered alone are typically within therange of about 0.5 μg/kg/day to about 200 μg/kg/day. Most preferably,the therapeutically effective amounts of D₂ agonist for humans andvertebrates when administered alone are typically within the range ofabout 1.0 μg/kg/day to about 150 μg/kg/day. Therapeutically effectiveamounts of D₁ agonist for humans and vertebrates when administeredparenterally alone (not conjoined to a D₂ agonist) are typically withinthe range of about 1.0 μg/kg/day to about 10.0 mg/kg/day. Preferably,the therapeutically effective amounts of D₁ agonist for humans andvertebrates when administered alone are typically within the range ofabout 1.0 μg/kg/day to about 10.0 mg/kg/day. More preferably, thetherapeutically effective amounts of D₁ agonist for humans andvertebrates when administered alone are typically within the range ofabout 1.0 μg/kg/day to about 7.0 mg/kg/day. Most preferably, thetherapeutically effective amounts of D₁ agonist for humans andvertebrates when administered alone are typically within the range ofabout 2.0 μg/kg/day to about 5.0 mg/kg/day.

Where therapeutically effective amounts of D₁ and D₂ agonist(s) forhumans and vertebrates are administered parenterally in conjunction,typically about 15% less of each of the D₁ and D₂ agonist(s) are used.Preferably, where therapeutically effective amounts of D₁ and D₂agonist(s) for humans and vertebrates are administered parenterally inconjunction about 17% less of each of the D₁ and D₂ agonist(s) are used.More preferably, where therapeutically effective amounts of D₁ and D₂agonist(s) for humans and vertebrates are administered parenterally inconjunction about 20% less of each of the D₁ and D₂ agonist(s) are used.Most preferably where therapeutically effective amounts of D₁ and D₂agonist(s) for humans and vertebrates are administered parenterally inconjunction about at least 25% less of each of the D₁ and D₂ agonist(s)are used.

D₁ dopamine agonists activate or potentiate D₁ dopamine receptors.Examples of D₁ agonists include, without limitation, dopamine,apomorphine, SKF38393, dihydrexidine, SKF 75670, SKF 82957, SKF 81297,SKF 82958, SKF 82598, A77636, A68930, and SKF 82526 (fenoldopam), andracemic trans-10, 11-dihydroxy 5, 6, 6a, 7, 8, 12b-hexahydro and relatedbenzazepine analogs, and those D₁ agonists disclosed in the referencescited herein. A preferred D₁ dopamine agonist is SKF 38393 orapomorphine. See e.g., U.S. Pat. No. 6,855,707, the contents of whichare incorporated herein in their entirety by reference.

D₂ dopamine agonists activate or potentiate D₂ dopamine receptors (e.g.,D₂, D₂ short and D₂ long receptors, D₄, and D₄ dopamine receptors). Inone embodiment, the D₂ agonist is a selective agonist for the D₂receptor over the D₁ receptor. In a further embodiment, the D₂ agonistis a weak D₁ agonist or is not a D₁ agonist.

Ergot-related D₂ agonists include, for example and without limitation,2-bromo-α-ergocriptine (bromocriptine), terguride, hydergine, 6-methyl 8β-carbobenzyloxy-aminoethyl-10-α-ergoline, 8-acylaminoergoline,6-methyl-8-α-(N-acyl)amino-9-ergoline, lisuride,dihydro-alpha-ergocriptine, dihydro-alpha-ergotoxine,6-methyl-8-α-(N-phenyl-acety)amino-9-ergoline, ergocornine,9,10-dihydroergocornine, any D-2-halo-6-alkyl-8-substituted ergoline,and D-2-bromo-6-methyl-8-cyanomethylergoline. Of these bromocriptine,terguride, lisuride, dihydroergotoxine (hydergine) or ergot-relatedcompounds with little or no serotonin 5HT_(2B) receptor agonist activityis most preferred.

Non-ergot-related dopamine D₂ agonists are selected from, for exampleand without limitation, ropinirole, piribedil, talipexole, quinelorane,and apomorphine.

A prolactin inhibitor (such as bromocriptine) can be administered to amammalian subject (particularly to a human) at a predetermined timeduring a 24-hour period if that subject has abnormally high daytimeprolactin levels (higher than any of the normal daytime levels for asubject of the same species and sex). The administration and its timingare designed to decrease the subject's abnormally high daytime prolactinlevels. However, a prolactin stimulator may need to be administered at adifferent predetermined time during a 24-hour period, if the subject hasabnormally low night-time prolactin levels, to increase these night-timeprolactin levels to be preferably no lower than the normal night-timeprolactin levels for the same sex. It is also possible that both aprolactin inhibitor and a prolactin stimulator may need to beadministered at different times to the same subject to bring about botha decrease in daytime prolactin levels and an increase in night-timeprolactin levels. Aberrations in the circadian rhythm of plasmaprolactin (and potentially glucocorticosteroid hormone as well) may be amarker of depression as well as of metabolic disease and “resetting” theplasma prolactin rhythm with dopamine agonist administration in themorning and serotonin enhancing antidepressant agonists administrationin the evening may provide additional therapeutic benefit to themetabolic disorder(s) and the depressed state.

The term “parenteral administration” is defined herein to mean a methodof administration that provides for the absorption of a substantialamount of the drug through other than the gastric and/or intestinalmucosa of the GI tract.

Routes of parenteral administration include, without limitation, buccal,sublingual, subcutaneous, nasal, oral, otic, ocular, rectal, vaginal, orupper respiratory mucosa, or through the skin or lungs. Accordingly, thedosage forms include, without limitation, injection, oral, otic,ophthalmic, or nasal sprays or drops, sublingual and/or buccal sprays,drops, tablets, solutions, colloidal suspensions, and/or ointments, hardcapsule and soft capsules, tablets, coated tablets, or sachets, lozenge,films, chewing gum, chewable tablet, liquid gargle, skin patch,ointment, lotion, or cream, a respiratory inhaler, aerosols, or rectalor vaginal suppository. Injection can be, for example, subcutaneous,intradermal, and/or intraperitoneal. Methods of nasal administrationinclude nasal sprays and/or drops and/or application of nasal ointments.Methods of sublingual or buccal administration include oral spays,drops, solutions, colloidal suspensions, tablets, ointments, lozenges,films, chewing gums, chewable tablets, and/or liquid gargle. Methods ofauricular or ocular administration include sprays, drops, ointments,lotions and/or creams. Methods of rectal administration includesuppository, spray, drops, ointment, lotion and/or cream. Methods ofvaginal administration include suppository, spray, drops, ointment,lotion and/or cream. Methods of upper respiratory mucosa or pulmonaryadministration include a respiratory inhaler, e.g., nebulizer. Methodsof transdermal administration include skin patches, dermal spray, drops,ointment, lotion, gel and/or cream.

Preferred routes of administration for dopamine receptor agonists aresubcutaneous injection, buccal, sublingual, nasal and transdermal. Morepreferred routes of administration are buccal, sublingual and nasal.Particularly preferred routes of administration include subcutaneousinjections, sublingual or buccal dosage forms, and transdermalapplication for example via skin patches.

Where parenteral administration is accomplished via oral administration,absorption through the gastric and/or intestinal mucosa can besubstantially prevented by the use of certain components in theformulation such as bioadhesives, permeabilizing agents and stabilizersthat prevent and/or reduce the introduction of dopamine agonists intothe gastric and/or intestinal mucosa of the GI tract.

The term “metabolic disorder” includes disorders associated withaberrant whole-body glucose, lipid and/or protein metabolism of aspecies and pathological consequences arising there from. Thesemetabolic disorders may or may not be associated with aberrant patternsin the daily levels (and fluctuations) of prolactin secretion.

The “key elements” of these metabolic disorders include but are notlimited to, Type 2 diabetes, prediabetes (impaired fasting glucose orimpaired glucose tolerance), metabolic syndrome or indices (keyelements) thereof (increased waist circumference, increased fastingplasma glucose, increased fasting plasma triglycerides, decreasedfasting high density lipoprotein level, increased blood pressure),insulin resistance, hyperinsulinemia, cardiovascular disease (or keyelements thereof such as arteriosclerosis, coronary artery disease,peripheral vascular disease, or cerebrovascular disease), congestiveheart failure, obesity, elevated plasma norepinephrine, elevatedcardiovascular-related inflammatory factors, elevated plasma factorspotentiating vascular endothelial dysfunction, hyperlipoproteinemia,arteriosclerosis or atherosclerosis, hyperphagia, hyperglycemia,hyperlipidemia, and hypertension or high blood pressure, increasedplasma postprandial triglyceride or free fatty acid levels, increasedcellular oxidative stress or plasma indicators thereof, increasedcirculating hypercoagulative state, renal disease including renalfailure and renal insufficiency.

As used herein, the term “pharmaceutically acceptable” refers to abiologically or pharmacologically compatible drug component for in vivouse, and preferably means a drug component approved by a regulatoryagency of the Federal or a state government or listed in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly in humans.

The term “bioavailability” refers to the rate and extent to which adopamine agonist is absorbed into a biological system from anadministered drug product and becomes available at the site ofbiological action.

As used herein, a “therapeutically effective amount” refers to theamount of an active agent, such as a dopamine receptor agonist or anantidepressant, sufficient to treat the targeted disease in the patient.

Prolactin Cycle & Dopamine Agonists

Healthy (normal) subjects, i.e., lean members of a species not sufferingfrom such metabolic disease and/or key elements thereof have highlypredictable daily prolactin release profiles. In humans these releaseprofiles are characterized by a low and relatively constant prolactinlevel during the waking hours (day) followed by a sharp rise to a peakduring sleep (night) and subsequent more gradual tapering down to thewaking hours level by morning. One or more dopamine receptor agonist canbe administered to a subject in need thereof to modify aberrant dailyprolactin level rhythms so that they resemble, or more closelyapproximate in phase and amplitude, the normal diurnal plasma prolactinlevel rhythms of lean, young and healthy members of the same species andsex. See e.g., U.S. Pat. Nos. 5,468,755; 5,496,803; 5,344,832,5,585,347, 5,830,895, and 6,855,707 and PCT applications US93/12701 andUS95/09061 (the disclosure of which is incorporated herein byreference). Such modulation of prolactin rhythms has been used to treatType 2 diabetes, obesity, insulin resistance, and hyperinsulinemia orhyperglycemia, hyperlipoproteinemia, hyperphagia, obesity, insulinresistance (impaired glucose tolerance), hyperlipidemia, etc.

A relationship exists between obesity and insulin resistance, and thatobesity can lead to increased insulin resistance. Likewise, thecircadian rhythms of plasma prolactin and glucocorticosteroidconcentrations, respectively, have important consequences in theregulation of body fat stores, and that the phase relationship betweenthe prolactin and glucocorticosteroid levels, respectively, differ inlean and fat animals. In a fat animal, prolactin will reach a peak levelat a given hour of a 24 hour period (in a human usually near midday),and the prolactin level of a lean animal at another time of day (in ahuman usually during sleep). In a lean animal the glucocorticosteroids,e.g., cortisol, will peak during a 24 hour period at a given hour(generally at a time different from that of prolactin); in a humangenerally within a few hours of waking. Thus, the phase relations of thecortisol and prolactin rhythms differ in lean and fat animals. The peakperiods of prolactin and glucocorticosteroid production, respectively,may differ to some extent between male and females of any given species.This being so, daily dosages of a dopamine agonist, or prolactininhibitor, given to an obese subject shortly after the normal time ofday that the prolactin is at its peak in a lean subject of the samespecies and sex will produce a weight reduction in the obese subject.Such treatment will, if continued over a sufficient period, reset on along term or permanent basis the phase of the neural oscillation for theprolactin rhythm, or the phases of the neural oscillations for both theprolactin and glucocorticosteroid rhythms in the obese individual tothat present in a lean subject. The obese subject, on initiation of thetreatment with the dopamine agonist, or prolactin inhibitor, will losebody fat stores, and the body fat deposits of the obese subject oncontinuation of the treatments on a daily basis will drop to andstabilize at that of a lean subject of the same species. Ondiscontinuing the daily treatments, the rise and fall of the prolactin,or prolactin and glucocorticosteroid levels in the blood of the treatedpatient on a daily basis will correspond to that of a lean subject ofthe same species, and for a period of long duration. The effect ofresetting the prolactin, or prolactin and glucocorticosteroid rhythms,in this manner also increases the sensitivity of the cells of thesubject to insulin, reduces hyperinsulinemia or hyperglycemia, or both,and thus alters long term pathologies which are characteristic of theonset of Type 2 diabetes. This effect of resetting the prolactin orprolactin and glucocorticosteriod rhythm, via timed daily administrationof dopamine receptor agonists and serotonin-enhancing agents may alsoimprove the depressed state as well.

Administration of Dopamine Agonist(s)

The amount of the dopamine agonist(s) to be administered to a patientmay vary, depending for example on the weight of the patient and thenature or severity of the metabolic disease or the key elements thereof.An effective amount of the dopamine agonist(s) may be administered inone or more dosage forms, either simultaneously or at different times,and a dopamine agonist may be administered either separately or inconjunction with other dopamine agonist(s).

Preferably, the dopamine receptor agonist(s) may be administered to apatient in need thereof in a single daily dose of about 0.01 to about50.0 mg of active agent. The preferred range is 0.02 to 50 mg of activeagent, the more preferred range is 0.02 to 25 mg of active agent and themost preferred range is 0.1 to 25 mg of active agent.

Conjoined administration of one or more dopamine D₁ agonist with one ormore D₂ agonist results in synergistic effects in improvement of one ormore metabolic indices related to glucose or lipid metabolism, and thusan improved modification or regulation of at least one of glucose andlipid metabolism.

The administration of the D₂ agonist is preferably timed. The D₂ agonistcan be administered at a predetermined time.

The administration of the D₁ agonist is preferably timed. The D₁ agonistis administered at a predetermined time. Because the D₁ agonistamplifies the effect of the conjoined D₂ agonist, it is advantageous toadminister the D₁ agonist at or about the time of administration of theconjoined D₂ agonist(s), such that the activity period of the D₁ agonistin the bloodstream of the treated subject overlaps (in fact preferablyoverlaps as much as possible) with the activity period of the conjoinedD₂ agonist(s).

Preferably, the dopamine receptor agonist(s) are administered oncedaily. More preferably, the dopamine receptor agonist(s) areadministered once daily in the morning. Most preferably, the dopaminereceptor agonist(s) are administered once daily at a predetermined timefor bioavailability in the morning at a point after the peak in plasmaprolactin level.

Dopamine receptor agonist(s) are preferably administered in the morningfrom about 0400 to about 1200 hour. More preferably, the dopaminereceptor agonist(s) are administered in the morning from about 0500 toabout 1200 hour. Most preferably, the dopamine receptor agonist(s) areadministered in the morning from about 0500 to about 1000 hour.

For treating vertebrates, dosages of dopamine agonists are typicallyadministered over a period ranging from about 10 days to about 180 days,or longer (e.g., greater than or equal to 1 year). However, patients,e.g., patients in particularly poor physical condition, or those ofadvanced age, may require longer, or even continuous, treatment. Atreatment duration exceeding six months or even continuous treatment maybe desirable, even when not required.

Administration of D₁ and D₂ agonists typically lead to improvement of atleast one condition or indices indicative of a metabolic disorder.

The methods of the present invention are particularly suited fortreatment of metabolic disorders and/or key elements of these disordersincluding but not limited to, Type 2 diabetes, prediabetes (impairedfasting glucose or impaired glucose tolerance), metabolic syndrome orindices (key elements) thereof (increased waist circumference, increasedfasting plasma glucose, increased fasting plasma triglycerides,decreased fasting high density lipoprotein level, increased bloodpressure), insulin resistance, hyperinsulinemia, cardiovascular disease(or key elements thereof such as arteriosclerosis, coronary arterydisease, peripheral vascular disease, or cerebrovascular disease),congestive heart failure, obesity, elevated plasma norepinephrine,elevated cardiovascular-related inflammatory factors,hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia,hyperlipidemia, and hypertension or high blood pressure, increasedplasma postprandial triglyceride or free fatty acid levels, increasedcellular oxidative stress or plasma indicators thereof, increasedcirculating hypercoagulative state, renal disease including renalinsufficiency.

Combination Therapy with Dopamine Agonists and Anti-Depressants

In preferred embodiments, patients suffering from a metabolic diseaseand depression are treated with a combination of a dopamine agonist andan anti-depressant. It has been found surprisingly that combinationtreatment of such patients is unexpectedly enhanced when a dopamineagonist is administered at a pre-determined first time of day and ananti-depressant is administered at a different, pre-determined secondtime of day, compared to administering the dopamine agonist and theanti-depressant at the same time of day.

A preferred pre-determined time of day for administering a dopamineagonist, e.g., when used in combination with an anti-depressant, is inthe morning, e.g., at 0400 to 1200 hours, preferably within 1-2 hoursand, more preferably, within 30 minutes of waking. A preferredpre-determined time for administering an anti-depressant, e.g., whenused in combination with a dopamine agonist, is at night, e.g., at 2000to 2400 hours, preferably within 1-2 hours and, more preferably, within30 minutes of bedtime.

In certain embodiments, a dopamine agonist is administered at apre-determined first time of day and an anti-depressant is administeredat a different, pre-determined second time of day, by administering asingle dosage form that provides for the release of a dopamine agonistand an anti-depressant at different times following administration.Thus, following administration, a dosage form may first release theanti-depressant, followed several hours later by the release of thedopamine agonist. Such a dosage form is preferably is taken at bedtimeto produce introduction to the circulation of the antidepressant ataround bedtime (around 2200 to 2400 hours) and introduction to thecirculation of the dopamine agonist within 0400 to 1200 hours willproduce the desired beneficial effect on metabolic disorders anddepression. Alternatively, following administration, a dosage form myfirst release the dopamine agonist, followed several hours later by therelease of the anti-depressant. Such a dosage is preferably is taken inthe morning, more preferably upon waking, e.g., at 0400 to 1200, hoursto produce introduction to the circulation of the dopamine agonist andintroduction of the anti-depressant several hours later, e.g., at aroundbedtime (around 2200 to 2400 hours).

Thus in certain embodiments, the invention provides a composition, e.g.,a dosage form, comprising a first active agent and a second activeagent, wherein said active agents are released at substantiallydifferent times following administration of the dosage form. In certainembodiments, the first and second active agents are substantiallyreleased, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 hours apart following administration of the dosageform. In certain embodiments, the first and second active agents aresubstantially released 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18,1-20, 2-4, 2-6, 2-8, 2-10, 2-12, 2-14, 2-16, 2-18, 2-20, 3-6, 3-8, 3-10,3-12, 3-14, 3-16, 3-18, 3-20, 4-8, 4-10, 4-12, 4-14, 4-16, 4-18, 4-20,6-10, 6-12, 6-14, 6-16, 6-18, 6-20, 8-10, 8-12, 8-14, 8-16, 8-18, 8-20,10-12, 10-14, 10-16, 10-18, 10-20, 12-14, 12-16, 12-18, 12-20, 14-16,14-18, 14-20, 16-18, 16-20 or 18-20 hours apart following administrationof the dosage form. In certain embodiments, said first active agent is adopamine agonist and second active agent is an anti-depressant. Incertain embodiments, said first active agent is an anti-depressant andsaid second active agent is a dopamine agonist. In a preferredembodiment said first active agent is an anti-depressant, said secondactive agent is a dopamine agonist and said active agents are released4-12 hours apart. In certain embodiments, said first active agent is adopamine agonist and said second active agent is an anti-depressant. Incertain embodiments said first active agent is a dopamine agonist, saidsecond active agent is an anti-depressant and said active agents arereleased 12-16 hours apart. More preferably each of said aforementioneddosage forms provide for the first active agent to be released within 2hours following administration of the dosage form. Also preferred aredosage forms wherein said first agent is an anti-depressant that isreleased within 2 hours following administration and said second activeagent is a dopamine agonist that is released within 2 hours of waking,when said dosage form is administered at bedtime.

In certain embodiments, a dopamine agonist and an anti-depressant areadministered in amounts that together constitute a therapeuticallyamount for treating a metabolic disorder and/or depression, but whichwould not separately constitute a therapeutic amount, i.e., either oneor both of the amount(s) of dopamine agonist and anti-depressant isadministered at a sub-threshold amount.

Administration of Anti-Depressants

Therapeutic administration of anti-depressants is well known in the art.Examples of anti-depressants and guidance on their use for treatingdepression is found, for example, in Baldessarini, R. J., (2006), DrugTherapy of Depression and Anxiety, Chapter 17 in Goodman & Gilman's, ThePharmacological Basis of Therapeutics, eleventh edition, Brunton, L. L.,et al. (ed.), Magraw-Hill, New York, pages 429-459, the content of whichis incorporated herein by reference in its entirety. Preferredanti-depressants for combination treatment with dopamine agonists areserotonin enhancing agents, e.g., SSRIs, serotonin, 5-hydroxytryptophan,and tryptophan, tricyclics, e.g., phenothiazines, tertiary aminetricyclics and secondary amine tricyclics, and atypicalanti-depressants. Examples of SSRIs include, without limitation,fluoxetine and paroxetine. Examples of tertiary amine tricyclicsinclude, without limitation, amitriptylen, doxepin, imipramine andtrimipramine. Examples of secondary amine tricyclics include, withoutlimitation, amoxapine, desipramine and nortiptyline. Examples ofatypical anti-depressants (including atypical anti-psychotics, seeBaldessarini et al., Pharmacotherapy of Psychosis and Mania, Chapter 18,pp. 461-500 in Goodman & Gilman, supra, the content of which isincorporated herein by reference in its entirety) include, withoutlimitation, duloxetine, and mirtazapine.

EXAMPLES

The following example represents certain embodiments of the invention.The example is illustrative only and is not intended to limit theinvention.

Example 1 Effect of Once-daily, Morning Administration of Dopamine D2Receptor Agonist on Depression Adverse Event Reporting Rate, AdverseCardiovascular Event Rate, and Hyperglycemia in Type 2 Diabetes Patients

A large proportion of subjects with type 2 diabetes have cardiovasculardisease (approximately 65% of subjects with type 2 diabetes die ofcardiovascular disease related events) and approximately 30% have someform of depression. The impact of Cycloset (a quick-release formulationof bromocriptine mesylate) upon hyperglycemia, adverse cardiovascularevent rate, and depression adverse event reporting rate was assessed ina broad population of subjects with type 2 diabetes, many of whichhaving cardiovascular disease risk factors, and many diagnosed withdepression at study entry.

A 52 week, double blind, 2:1 randomized, multicenter study was conductedin patients with type 2 diabetes receiving a diabetes therapeuticregimen consisting of diet or no more than two hypoglycemic agents orinsulin with or without one additional oral agent that were randomizedto treatment with Cycloset (titrated from 1.6 mg/day to a maximaltolerated dose up to 4.8 mg daily; n=2,054), or placebo (n=1,016) (TheCycloset Safety Trial). Subjects were instructed to take their studydrug (Cycloset or placebo) once daily in the morning upon awakening. Ifthe subject missed taking the study drug within two hours of awakening,the subject was instructed to skip that day's dose and resume dosing thenext morning. Subjects taking serotonin-potentiating anti-depressantswere instructed to take such medications in the evening unlesscontraindicated to do so by sound medical practice or drug labeling.Inclusion criteria included subjects aged 30-80 with Type 2 diabetes, anHbA1C of <10.0 and BMI<43. All adverse events were recorded byinvestigational site personnel from hospital records, subject-derivedinformation, or subject-associated health care individuals associatedwith the event, per the specified study protocol and subject InformedConsent Form and in compliance with ICH guidelines and Good ClinicalPractice Standards.

The primary and secondary endpoints were time to first all-cause seriousadverse event (SAE) and cardiovascular SAE (composite of myocardialinfarction, stroke, coronary revascularization, hospitalization forangina and hospitalization for congestive heart failure), respectively,which were adjudicated by an independent review committee. Apre-specified analysis of the between-treatment differences in HbA1cfollowing 24 weeks of therapy among a subpopulation of subjectsreceiving metformin and sulfonylurea and HbA1c of >7.5 at baseline wasalso performed.

There were 176 Cycloset and 98 placebo subjects that experienced a SAE,yielding a rate ratio of 0.88 and a hazard ratio of all cause SAE of1.023 (96% one sided confidence limit of 1.27). There were 31 (1.5%)cardiovascular SAEs in the Cycloset group and 30 (3.0%) events in theplacebo group resulting in a 42% reduction in cardiovascular outcomes inCycloset treated subjects versus placebo (HR=0.58, 95% CI: 0.35-0.96;P=0.036). The incidence rate ratio for each of the components of thecardiovascular composite was less than 1.0. Among the metformin andsulfonylurea treated subpopulation of subjects, Cycloset (n=121)treatment resulted in an HbA1c reduction of −0.674 from baseline versusan increase for placebo (n=71) of 0.015 to give a placebo-adjustedchange from baseline of −0.69 (P<0.0002). Of these Cycloset treatedsubjects, 39% (vs. 11% placebo) reached the American DiabetesAssociation goal of HbA1c<7.0 (P<0.0007) and 53% (vs. 21% placebo)experienced a minimum reduction in HbA1c from baseline of 0.7(p<0.0001).

Cycloset significantly reduced the risk for the a priori adjudicatedcardiovascular adverse event endpoint and was comparable to placebo forall other serious adverse events for the entire study population. Amongindividuals inadequately controlled on metformin and sulfonylurea, 24weeks of Cycloset therapy significantly improved glycemic controlrelative to placebo.

Cycloset had a statistically significant benefit on the pre-specifiedCVD composite endpoint of myocardial infarction (MI), stroke, coronaryrevascularization, hospitalization for angina or congestive heartfailure (42% risk reduction [RR]; p=0.036). Another analysis includes apost-hoc analysis from this Cycloset Safety Trial that assesses theeffect of Cycloset on the time to first occurrence of major adversecardiovascular events (MACE) defined as the composite of MI, stroke andCVD death and additional planned analysis of the influence of Cycloseton the CVD composite endpoint stratified by the baseline median HbA1c.CVD risk estimates were estimated as a hazard ratio [HR] and 95%confidence interval [CI] on the basis of the Cox proportional-hazardsregression. Cycloset had a statistically significant beneficial effecton the risk of myocardial infarction, stroke and CVD death (55% RR;p=0.049). Among subjects with HbA1c<7.0 there were fewer CVD events onCycloset (15, n=1219) compared to placebo (18, n=615). For those withHbA1c>7.0 CVD events were also less on Cycloset (16, n=830) compared toplacebo (12, n=400). The HR of the CVD composite endpoint for subjectswith a baseline HbA1c of <7.0 or >7.0 was 0.48 (95% CI 0.24-0.95) or0.74 (95% CI 0.35-1.56), respectively. Additionally, the beneficialreduction in the CVD composite endpoint was apparent regardless of age,gender or race. Cycloset significantly reduced the risk for myocardialinfarction, stroke, and cardiovascular death. The macrovascular riskreduction for the pre-specified cardiovascular composite endpoint wasapparent even among subjects with good glycemic control.

The number of adverse events related to depression, adjustment disorder,depressed mood, and suicide attempt, and the number of serious adverseevents related to depression, suicide, and suicide attempt are reportedin Table 1, below.

TABLE 1 Type 2 diabetic subjects exposed to Cycloset experienceddepression-related adverse events at rate 48% less than when exposed toplacebo. Cycloset Placebo Adverse Events Reported (2054 subjects) (1016subjects) Depression 13 12 Adjustment disorder with 0 1 depressed moodDepressed mood 2 1 Suicide attempt 0 2 Serious Adverse Events ReportedCycloset Placebo Depression 2 0 Suicide 1 0 Suicide attempt 0 1 TOTALSCycloset Placebo # of Adverse or Serious Adverse 18 17 Events Reported %of subjects reporting 0.87 (18/2054) 1.67 (17/1016)

The incidence of adverse event reporting for depression,depression-related symptoms, suicide, and suicide attempts wassubstantively reduced among Type 2 diabetes subjects treated withCycloset versus placebo. Also, glycemic control was significantlyimproved in the Cycloset group versus the placebo control group, asevidenced in part by a relative reduction in HbA1c level.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed various modifications of theinvention in addition to those described herein will be apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

It is further to be understood that all values are approximate and areprovided for description. All references cited and discussed in thisspecification are incorporated herein by reference in their entirety andto the same extent as if each reference was individually incorporated byreference.

What is claimed is:
 1. A dosage form for administration to type IIdiabetic patients suffering from depression comprising a first activeagent and a second active agent, wherein said first active agent is aserotonin enhancing agent, said second active agent is a dopamineagonist, said first active agent is substantially released within 2hours following administration of said dosage form and said secondactive agent is released substantially within the period within 2 hoursof waking when said dosage is administered at bedtime.
 2. The dosageform of claim 1 wherein the first active agent comprises anantidepressant.
 3. The dosage form of claim 1 wherein the dopamineagonist is an ergot related dopamine D2 agonist.
 4. The dosage form ofclaim 1 wherein the dopamine agonist is an ergot related dopamine D2agonist.
 5. The dosage form of claim 1 wherein the dopamine agonist is aDI dopamine agonist.
 6. The dosage form of claim 1 wherein the dopamineagonist is a D2 dopamine agonist.
 7. The dosage form of claim 5 whereinthe DI dopamine agonist is SKF
 38393. 8. The dosage form of claim 5wherein the DI dopamine agonist is apomorphine.
 9. The dosage form ofclaim 1 wherein the first active agent is a selective serotonin reuptakeinhibitor.
 10. The dosage form of claim 9 wherein the selectiveserotonin reuptake inhibitor is fluoxetine.